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LTLD in combination with MR-HIFU induced hyperthermia and cyclophosphamide

Single arm study

Patients will receive up to six cycles at three-weeks intervals of:

* Intravenous LTLD dosed at 50mg/m2 administered during the MR-HIFU treatment
* 60 minutes of MR-HIFU mild local hyperthermia at 40 °C - 42 °C to the primary breast tumour
* Intravenous Cyclophosphamide 600 mg/m2 after MR-HIFU treatment

In case of toxicity, LTLD, cyclophosphamide and/or hyperthermia dosages will be adjusted as specified in the study protocol.

LTLD

Patients will receive up to six cycles at three-weeks intervals of:

- 60 minutes of MR-HIFU mild local hyperthermia at 40 °C - 42 °C to the primary breast tumour.

In case of toxicity, hyperthermia dosages will be adjusted as specified in the study protocol.

MR-HIFU induced hyperthermia

Patients will receive up to six cycles at three-weeks intervals of:

- Intravenous Cyclophosphamide 600 mg/m2 after MR-HIFU treatment

In case of toxicity, cyclophosphamide dosages will be adjusted as specified in the study protocol.

Mirjam A de Visser, MD

Britt BM Suelmann, MD

In this phase I feasibility study, the investigators evaluate the combination of lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox) with local hyperthermia and cyclophosphamide (C), for the local treatment of the primary breast tumour in patients with metastatic breast cancer.

When heated to 40-43 degrees Celsius (ºC), LTLD releases a very high concentration of doxorubicin locally within seconds. Hyperthermia of the primary tumour will be induced by Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU) on a dedicated Sonalleve MR-HIFU breast system.

The investigators hypothesize that by substituting doxorubicin (A) in the AC-chemotherapy regimen for the combination of LTLD and MR-HIFU induced hyperthermia, optimal local tumour control can be achieved without compromising systemic toxicity or efficacy.

This will be the first study to evaluate LTLD with MR-HIFU hyperthermia in breast cancer patients.

Advances in systemic treatment led to improved overall survival in patients with metastatic breast cancer. Various studies suggest that by obtaining loco-regional control, overall survival in advanced disease can further be improved.

Pre-operative chemotherapy can be used in metastatic breast cancer to make radical removal of the primary tumor feasible, while simultaneously maintaining control of already present metastatic sites. The doxorubicin and cyclophosphamide regimen (AC) is well-known both in (neo-)adjuvant setting as in treatment of metastatic breast cancer. At present, optimal local control in advanced breast cancer using adequate dosing of doxorubicin is hampered by its toxic systemic effects. Therefore the investigators aim to increase doxorubicin deposition in the primary tumor without interfering with systemic efficacy and toxicity, by combining lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox) with local mild hyperthermia, induced by Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU). When heated to 40-43 ºC, ThermoDox releases a very high concentration of doxorubicin locally within seconds. In the absence of hyperthermia, ThermoDox leads to a similar biodistribution and antitumor efficacy to free doxorubicin. MR-HIFU allows for controlled heating of deep-seated tumors.

This is a single-arm phase I feasibility study in 12 patients with de novo stage IV (distant metastasis at the time of diagnosis) her2-negative breast cancer, who have not received previous chemotherapy. The study treatment consists of up to 6 cycles at 21-day intervals of ThermoDox (50mg/m2) administered during MR-HIFU induced hyperthermia (60 minutes at 40-42 ᵒC) and cyclophosphamide (600 mg/m2) administered afterwards. A dedicated MR-HIFU breast system integrated with a clinical 1.5 Tesla Magnetic Resonance Imaging (MRI) scanner will be used for safe and controlled heating of the tumour. Primary endpoints are safety, tolerability and feasibility. Secondary endpoint is efficacy, assessed by radiological response of the local tumor and the distant metastases.

In the Biobank side study, extra blood samples will be collected. These samples will be used for further research on not yet determined topics related to breast cancer.

Image-guided Targeted Doxorubicin Delivery With Hyperthermia to Optimize Loco-regional Control in Breast Cancer

Image-guided Targeted Doxorubicin Delivery With Hyperthermia to Optimize Loco-regional Control in Breast Cancer. Phase I Feasibility Study of Hifu-Induced Hyperthermia, LTLD and Cyclophosphamide for Metastatic Breast Cancer

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Image-guided Targeted Doxorubicin Delivery With Hyperthermia to Optimize Loco-regional Control in Breast Cancer	NCT03749850	Metastatic Brea... Breast Cancer Breast Neoplasm... Stage IV Breast... Metastatic Canc... Invasive Ductal... Invasive Ductal... Adenocarcinoma ...	LTLD MR-HIFU induced... Cyclophosphamid...	18 Years -	UMC Utrecht
Image-guided Targeted Doxorubicin Delivery With Hyperthermia to Optimize Loco-regional Control in Breast Cancer	NCT03749850	Metastatic Brea... Breast Cancer Breast Neoplasm... Stage IV Breast... Metastatic Canc... Invasive Ductal... Invasive Ductal... Adenocarcinoma ...	LTLD MR-HIFU induced... Cyclophosphamid...	18 Years -	UMC Utrecht

Spots Global Cancer Trial Database for de novo stage iv